Heat shock proteins (HSPs) are a group of proteins induced by elevated temperatures or other stress. The most prominent HSPs are a class of functionally-related proteins involved in maintenance and remodelling of protein three-dimensional structure. Heat shock protein 90 (HSP90) is an ATP-dependent molecular chaperone that plays a central role in regulating the correct folding, stability, and function of numerous “client proteins,” including human epidermal growth factor receptor 2 (HER2), BRAF, mutant EGFR, EML4-ALK, Bcr-Abl, Raf-1, and ABL, which are required for cancer cell survival. HPS 90 also is a known chaperone of AR (androgen receptor). Elevated, abnormal levels of HSP90 have been observed in human prostatic carcinoma (Palmieri et al 2014). It has also been reported that many oncogenic proteins essential for cancer transformation are chaperoned by the Hsp90 complex, and some of these client proteins have been discovered by using Hsp90 inhibitors, such as geldanamycin and radicicol.
In vitro studies show that inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor, and thereby inhibits breast tumor progression (Schultz et al 2012). Ex-vivo and in vitro studies of Hsp90 Inhibitors NVP-AUY922 and NVP-HSP990 were evaluated in the prostate cancer cell lines PC-3, LNCaP, and VCaP, and in an ex vivo culture model of human prostate cancer (Centenera et al 2012).
Due to its effect on a wide range of client proteins required for malignancy survival, HSP90 presents a potentially significant target for cancer treatment. Accordingly, a need exists for HSP90 targeting agents.